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The Journal of neuroscience : the official journal of the Society for Neuroscience v.37 no.4, 2017년, pp.871 - 881   SCI SCIE
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TNF-α Differentially Regulates Synaptic Plasticity in the Hippocampus and Spinal Cord by Microglia-Dependent Mechanisms after Peripheral Nerve Injury

Liu, Yong (Pain Research Center and Department of Physiology, Zhongshan School of Medicine of Sun Yat-sen University, Guangzhou 510080, China, ) ; Zhou, Li-Jun (Pain Research Center and Department of Physiology, Zhongshan School of Medicine of Sun Yat-sen University, Guangzhou 510080, China, ) ; Wang, Jun (Pain Research Center and Department of Physiology, Zhongshan School of Medicine of Sun Yat-sen University, Guangzhou 510080, China, ) ; Li, Dai (Pain Research Center and Department of Physiology, Zhongshan School of Medicine of Sun Yat-sen University, Guangzhou 510080, China, ) ; Ren, Wen-Jie (Pain Research Center and Department of Physiology, Zhongshan School of Medicine of Sun Yat-sen University, Guangzhou 510080, China, ) ; Peng, Jiyun (Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey 08854, ) ; Wei, Xiao (Pain Research Center and Department of Physiology, Zhongshan School of Medicine of Sun Yat-sen University, Guangzhou 510080, China, ) ; Xu, Ting (Pain Research Center and Department of Physiology, Zhongshan School of Medicine of Sun Yat-sen Univ ) ; Xin, Wen-Jun ; Pang, Rui-Ping ; Li, Yong-Yong ; Qin, Zhi-Hai ; Murugan, Madhuvika ; Mattson, Mark P. ; Wu, Long-Jun ; Liu, Xian-Guo ;
  • 초록  

    Clinical studies show that chronic pain is accompanied by memory deficits and reduction in hippocampal volume. Experimental studies show that spared nerve injury (SNI) of the sciatic nerve induces long-term potentiation (LTP) at C-fiber synapses in spinal dorsal horn, but impairs LTP in the hippocampus. The opposite changes may contribute to neuropathic pain and memory deficits, respectively. However, the cellular and molecular mechanisms underlying the functional synaptic changes are unclear. Here, we show that the dendrite lengths and spine densities are reduced significantly in hippocampal CA1 pyramidal neurons, but increased in spinal neurokinin-1-positive neurons in mice after SNI, indicating that the excitatory synaptic connectivity is reduced in hippocampus but enhanced in spinal dorsal horn in this neuropathic pain model. Mechanistically, tumor necrosis factor-alpha (TNF-α) is upregulated in bilateral hippocampus and in ipsilateral spinal dorsal horn, whereas brain-derived neurotrophic factor (BDNF) is decreased in the hippocampus but increased in the ipsilateral spinal dorsal horn after SNI. Importantly, the SNI-induced opposite changes in synaptic connectivity and BDNF expression are prevented by genetic deletion of TNF receptor 1 in vivo and are mimicked by TNF-α in cultured slices. Furthermore, SNI activated microglia in both spinal dorsal horn and hippocampus; pharmacological inhibition or genetic ablation of microglia prevented the region-dependent synaptic changes, neuropathic pain, and memory deficits induced by SNI. The data suggest that neuropathic pain involves different structural synaptic alterations in spinal and hippocampal neurons that are mediated by overproduction of TNF-α and microglial activation and may underlie chronic pain and memory deficits. SIGNIFICANCE STATEMENT Chronic pain is often accompanied by memory deficits. Previous studies have shown that peripheral nerve injury produces both neuropathic pain and memory deficits and induces long-term potentiation (LTP) at C-fiber synapses in spinal dorsal horn (SDH) but inhibits LTP in hippocampus. The opposite changes in synaptic plasticity may contribute to chronic pain and memory deficits, respectively. However, the structural and molecular bases of these alterations of synaptic plasticity are unclear. Here, we show that the complexity of excitatory synaptic connectivity and brain-derived neurotrophic factor (BDNF) expression are enhanced in SDH but reduced in the hippocampus in neuropathic pain and the opposite changes depend on tumor necrosis factor-alpha/tumor necrosis factor receptor 1 signaling and microglial activation. The region-dependent synaptic alterations may underlie chronic neuropathic pain and memory deficits induced by peripheral nerve injury.


  • 주제어

    memory deficit .   microglia .   neuropathic pain .   SNI .   synaptic plasticity .   TNF-α.  

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